Second-Hand Melanoma Melanosomes Regulate Diversity Among Tumor-Associated Macrophages

ABSTRACT: Extracellular vesicles (EVs) are a key form of cell-to-cell communication. Here we reveal a new mode of communication involving the large EVs, melanosomes. Unlike small EVsexosomes, which are dissolved in the receiver cell, melanosomes stay intact within them, gain a unique protein signature, and can then be further transferred to another cell, a state we term “second-hand EVs”. We found that melanoma-secreted melanosomes uptaken by and then released from epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages. The respective consequence for macrophages is polarization into pro-tumor or pro-immune-cell-infiltration phenotypes. Fibroblasts load melanosomes with AKT1, which induces VEGF secretion from macrophages in an mTOR-dependent manner, promoting angiogenesis and metastasis in-vivo. In melanoma patients, macrophages co-localized with AKT1, were correlated with disease aggressiveness, and immunotherapy non-responders were enriched in macrophages containing melanosome markers. Thus, the network of interactions via second-hand EVs helps form the metastatic niche. Since macrophage heterogeneity is pivotal in advancement of cancer, our data suggest an opportunity to halt melanoma progression by blocking the melanosome cues of macrophage diversification.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Tamar Ziv  

LAB HEAD: Carmit Levy

PROVIDER: PXD046421 | Pride | 2023-12-31

REPOSITORIES: Pride